Ketamine - Drug Monograph

Introduction

Ketamine is a dissociative anesthetic agent first synthesized in 1962 and approved by the FDA in 1970. Originally developed as a safer alternative to phencyclidine (PCP), ketamine has evolved from primarily an anesthetic agent to a medication with diverse applications in pain management, emergency medicine, and psychiatry. Its unique mechanism of action and favorable safety profile have established it as an essential medication on the World Health Organization's List of Essential Medicines.

Mechanism of Action

Ketamine primarily functions as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, blocking glutamate binding and reducing excitatory neurotransmission. This action produces dissociative anesthesia, characterized by functional dissociation between thalamocortical and limbic systems. Additionally, ketamine demonstrates activity at opioid receptors, monoaminergic receptors, muscarinic receptors, and voltage-sensitive calcium channels. Recent research has highlighted its role in promoting synaptogenesis through increased brain-derived neurotrophic factor (BDNF) signaling, which may underlie its rapid antidepressant effects.

Indications

• Induction and maintenance of general anesthesia
• Procedural sedation and analgesia

• Treatment-resistant depression (particularly as esketamine nasal spray)
• Chronic pain syndromes (including neuropathic pain and complex regional pain syndrome)
• Status asthmaticus (severe asthma exacerbation)
• Acute agitation in emergency settings
• Migraine headache treatment
• Rapid-sequence intubation adjunct

Dosage and Administration

• IV: 1-2 mg/kg (produces surgical anesthesia within 30 seconds lasting 5-10 minutes)
• IM: 3-8 mg/kg (produces surgical anesthesia within 3-4 minutes lasting 12-25 minutes)

• IV: 0.5-1 mg/kg initial dose, followed by 0.25-0.5 mg/kg increments as needed
• IM: 2-4 mg/kg for single administration

• Esketamine nasal spray: 28-84 mg administered twice weekly under supervision

• Hepatic impairment: Dose reduction recommended
• Renal impairment: Dose reduction recommended
• Elderly: Lower initial doses recommended (20-50% reduction)
• Pediatric: Similar mg/kg dosing as adults

Pharmacokinetics

Contraindications

• Known hypersensitivity to ketamine or any component of the formulation
• Significant hypertension (SBP >160 mmHg, DBP >100 mmHg)
• Elevated intracranial pressure (except in monitored settings with appropriate ventilation)
• Severe cardiac dysfunction including uncompensated heart failure
• History of psychosis (relative contraindication for psychiatric use)
• Acute porphyria

Warnings and Precautions

• Emergence reactions: May include vivid dreams, hallucinations, or delirium (more common in adults)
• Increased intracranial pressure: Use with caution and appropriate monitoring
• Hypertension and tachycardia: Monitor cardiovascular status
• Respiratory depression: Can occur with rapid IV administration or concomitant sedatives
• Ulcerative cystitis: Reported with chronic abuse; monitor urinary symptoms
• Hepatotoxicity: Monitor liver function with prolonged use
• Dependence potential: Schedule III controlled substance with abuse potential

Drug Interactions

• CNS depressants: Enhanced sedative effects (benzodiazepines, opioids, alcohol)
• Sympathomimetics: Increased cardiovascular effects
• Theophylline: May lower seizure threshold
• CYP3A4 inhibitors: Increased ketamine levels (ketoconazole, clarithromycin)
• CYP3A4 inducers: Decreased ketamine levels (rifampin, carbamazepine)
• Lamotrigine: May reduce ketamine's antidepressant effects
• St. John's Wort: May reduce ketamine concentrations

Adverse Effects

• Dizziness, drowsiness
• Nausea, vomiting
• Diplopia, nystagmus
• Increased salivation
• Psychotomimetic effects (dream-like state, dissociation)

• Hypertension, tachycardia
• Respiratory depression
• Emergence agitation
• Rash, injection site reactions

• Laryngospasm
• Anaphylaxis
• Intracranial hypertension exacerbation
• Ulcerative cystitis (chronic use)
• Hepatotoxicity

Monitoring Parameters

• Vital signs: BP, HR, RR, SpO2 continuous monitoring during administration
• Mental status: Assess for emergence reactions during recovery
• Respiratory function: Continuous monitoring, especially with concomitant sedatives
• Pain assessment: When used for analgesia
• Psychiatric status: For depression treatment (PHQ-9, mood assessment)
• Liver function: Periodic monitoring with chronic use
• Urinary symptoms: With long-term use (frequency, urgency, dysuria)

Patient Education

• Do not operate machinery or drive for 24 hours after administration
• Expect temporary dissociative effects that typically resolve within hours
• Report any persistent psychological effects or unusual thoughts
• Inform all healthcare providers of ketamine use, especially before procedures
• For depression treatment: attend all scheduled follow-up appointments
• Avoid alcohol and other CNS depressants for 24 hours after administration
• Report urinary symptoms immediately (frequency, pain, blood in urine)
• Notify provider if pregnant or planning pregnancy

References

1. Domino EF. Taming the ketamine tiger. Anesthesiology. 2010;113(3):678-684. 2. Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23(4):801-811. 3. FDA. SPRAVATO® (esketamine) prescribing information. 2020. 4. Jonkman K, van Rijnsoever E, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2017;83(7):1435-1446. 5. Jilani TN, Gibbons JA, Faizy RM, et al. Ketamine. [Updated 2023 May 26]. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024. 6. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74(4):399-405. 7. Green SM, Roback MG, Kennedy RM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med. 2011;57(5):449-461.